This invention concerns a series of novel xcex2-hydroxy aryloxypropylamines which are effective pharmaceuticals for the treatment of conditions related to or affected by the dopamine D2 receptor and also by the serotonin 1A receptor subtype. The compounds are particularly useful for the treatment of schizophrenia and related psychotic disorders and other conditions such as Parkinson""s disease and Alzheimer""s disease.
In their letter to the editor, TINS, Vol. 17, No. 4, 1994, Bowen et al. note that the cognitive impairment characteristics of Alzheimer""s disease may be ameliorated by antagonists at the inhibitory 5-HT1A receoptor, or by activation of the phospholipase-C-linked cholinergic M1 receptor.
This invention relates to novel indolyl derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in therapy. The compounds are useful for the treatment of psychotic disorders, particularly schizophrenia, by virtue of their ability to antagonize the dopamine D2 receptor. Furthermore, the present invention also provides compounds that are antagonists and agonists at the 5-HT1A receptor subtype and thus compounds of this invention may be used to treat Alzheimer""s Disease, Parkinson""s Disease, depression and anxiety.
Compounds of the present invention are represented by the general formula (1): 
wherein
R1 and R2 are each independently selected from H, OH, F, Cl, Br, I, 1 to 6 carbon alkyl or alkenyl, 1 to 6 carbon alkoxy, aryl, OR5, nitro, amino, CF3 and when R1 and R2 are taken together, form a fused ring at the 2,3- or 3,4-positions providing a fused phenyl group or a benzodioxane group, or a 4- or 7-substituted indole group, or a 5- or 8-substituted quinoline group;
the group formed by the fusion of R1 and R2 being taken together is further optionally substituted by from 1 to 3 groups selected from H, COOH or the C1 to C6 alkyl esters thereof, OH, F, Cl, Br, I, 1 to 6 carbon alkyl or alkenyl, 1 to 6 carbon alkoxy, OR5, xe2x80x94C(O)NR6R7, nitro, amino, or CF3;
R3 represents a group selected from hydrogen, 1 to 6 carbon alkyl, 1 to 4 carbon alkoxy or halogen;
R4 represents a group selected from hydrogen, 1 to 6 carbon alkyl or R5;
R5 is CH2Ph in which the phenyl ring can be optionally substituted by a group selected from OMe, halogen, CF3;
R6 and R7 are independently selected from H or C1 to C6 alkyl;
X is selected from a group represented by CR4, CHR4 and CHCH;
A is selected from a group represented by N, NIH, CH and CH2;
B is selected from a group represented by xe2x95x90O, xe2x95x90S, H and H2;
or A and B may be concatenated together to form indole, benzimidazole, indolone or indoline moieties; or a pharmaceutically acceptable salt thereof.
It will be understood that the type of substitution indicated by B in the generic groups herein will be controlled by whether A is N, NH, CH or CH2.
The moieties in which A and B may be concatenated together in formula (1) may be represented by the formula: 
which includes moieties selected from the group of: 
wherein the substituents indicated by R3 and R4 are as defined above.
In the description above, when R1 and R2 are taken together to form a fused phenyl group at the 2,3- or 3,4-positions, the two fused phenyl rings are understood to form a napthyl moiety, optionally substituted by from 1 to 3 groups described above.
The description above states the fusion of R1 and R2 with their corresponding phenyl ring may form a 4- or 7-substituted indole group, or a 5- or 8-substituted quinoline group. In this description, the 4- or 7-positions indicated for the indole group and 5- or 8-positions indicated for the quinoline group indicate the position at which the relevant indole or quinoline moiety is bound to the remainder of the molecule of Formula (1).
The term xe2x80x9carylxe2x80x9d as used in the definitions of R1 and R2 indicates phenyl, benzyl, benzyloxy or pyridine groups, optionally substituted by from 1 to 3 substitutents selected from halogen, C1-C6alkyl, C1-C6alkoxy, xe2x80x94Sxe2x80x94C1-C6alkyl, xe2x80x94CN, xe2x80x94OH, xe2x80x94NO2 or xe2x80x94CF3. The most preferred aryl group is phenyl, optionally substituted as just described.
A subset of compounds of this invention includes those of the formula: 
wherein
R1 and R2 are each independently selected from H, OH, F, Cl, Br, I, 1 to 6 carbon alkyl or alkenyl, 1 to 6 carbon alkoxy, OR5, nitro, amino, CF3, phenyl, benzyl, benzyloxy or pyridyl, the aromatic rings of which are optionally substituted by from 1 to 3 substitutents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94Sxe2x80x94C1-C6 alkyl, xe2x80x94CN, xe2x80x94OH, xe2x80x94NO2 or xe2x80x94CF3; or R1 and R2 are taken together to form, in conjunction with the phenyl ring to which they are bound, a fused ring at the 2,3- or 3,4-positions providing a fused phenyl group or a benzodioxane group, or a 4- or 7-substituted indole group, or a 5- or 8-substituted quinoline group;
the group formed by the fusion of R1 and R2 being taken together is further optionally substituted by from 1 to 3 groups selected from H, COOH or the C1 to C6 alkyl esters thereof, OH, F, Cl, Br, I, 1 to 6 carbon alkyl, alkenyl or alkoxy, xe2x80x94C(O)NR6R7, nitro, amino, or CF3;
R3 represents a group selected from hydrogen, a 1 to 6 carbon alkyl, a 1 to 4 carbon alkoxy or a halogen;
R4 represents a group selected from hydrogen, 1 to 6 carbon alkyl or R5;
R5 is CH2Ph in which the phenyl ring can be optionally substituted by a group selected from OMe, halogen, CF3;
R6 and R7 are independently selected from H or C1 to C6 alkyl;
A is selected from a group represented by N, NH, CH and CH2;
B is selected from a group represented by xe2x95x90O, xe2x95x90S, H and H2;
or A and B may be concatenated together such that the moiety in formula (1) represented by the formula: 
is selected from the group of: 
or a pharmaceutically acceptable salt thereof.
The pharmaceutically acceptable salts are the acid addition salts which can be formed from a compound of the above general formula and a pharmaceutically acceptable inorganic acid such as phosphoric, sulfuric, hydrochloric, hydrobromic citric, maleic, fumaric, acetic, lactic or methanesulfonic acid.